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Experimental parathyroid hormone gene therapy using ØC31 integrase.

 Sihoon LEE  ;  Soon Won HONG  ;  Han Seok CHOI  ;  Lee Young LEE  ;  Chunja NAM  ;  Yumie RHEE  ;  Ung-il CHUNG  ;  Sung-Kil LIM 
 ENDOCRINE JOURNAL, Vol.55(6) : 1033-1041, 2008 
Journal Title
Issue Date
Animals ; Attachment Sites, Microbiological/genetics ; Bacteriophages/genetics ; Cells, Cultured ; Culture Media/chemistry ; Genetic Therapy/methods* ; Humans ; Hypoparathyroidism/blood ; Hypoparathyroidism/genetics ; Hypoparathyroidism/pathology ; Hypoparathyroidism/therapy* ; Integrases/genetics* ; Integrases/physiology ; Liver/metabolism ; Liver/pathology ; Male ; Mice ; Mice, Inbred ICR ; Models, Theoretical ; Mutagenesis, Insertional/methods ; Parathyroid Hormone/analysis ; Parathyroid Hormone/blood ; Parathyroid Hormone/genetics* ; Parathyroid Hormone/metabolism ; Treatment Outcome
Gene therapy ; Parathyroid hormone ; Hypoparathyroidism ; ØC31 integrase
ØC31 integrase can integrate targeted plasmid DNA into preferred locations in mammalian genomes, resulting in robust, long-term expression of the integrated transgene. This system represents an effective tool that opens up promising possibilities for gene therapy. The classical treatment for hypoparathyroidism was calcium and vitamin D replacement. Recently, parathyroid hormone (PTH) replacement was reported to be a more potentially physiologic treatment option. However, PTH synthesis is technically difficult and costly. These issues may be minimized by using PTH gene therapy. We attempted to achieve site-specific genomic integration of the PTH gene into a human cell line and mice using this system. We cotransfected 293 HEK cells with PTH-attB plasmid with or without ØC31 integrase plasmid. Expression and secretion of PTH into culture supernatants and site-specific genomic integration of PTH cDNA were assessed by immunoradiometric assays and pseudo-site analysis, respectively. In in vivo experiments, we injected the PTH-attB plasmid with or without ØC31 integrase plasmid into a mouse tail vein using the hydrodynamic method. Plasma PTH concentrations were serially measured, and site-specific integration of PTH cDNA into the mouse genome was confirmed by examining hepatic genomic DNA. PTH was expressed and secreted from 293 HEK cells and mouse hepatocytes, and pseudo-site analysis confirmed the site-specific integration of PTH cDNA into the host genomes. The site-specificity and efficiency of this system are advantageous in many areas, including, potentially, gene therapy. PTH gene therapy is one candidate; however, for clinical applications, we need to regulate PTH expression and secretion in the future.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Rhee, Yumie(이유미) ORCID logo https://orcid.org/0000-0003-4227-5638
Lim, Sung Kil(임승길)
Choi, Han Seok(최한석)
Hong, Soon Won(홍순원) ORCID logo https://orcid.org/0000-0002-0324-2414
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